EP0489579B1 - Dérivés peptidyliques - Google Patents

Dérivés peptidyliques Download PDF

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Publication number
EP0489579B1
EP0489579B1 EP91311254A EP91311254A EP0489579B1 EP 0489579 B1 EP0489579 B1 EP 0489579B1 EP 91311254 A EP91311254 A EP 91311254A EP 91311254 A EP91311254 A EP 91311254A EP 0489579 B1 EP0489579 B1 EP 0489579B1
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Prior art keywords
group
formula
amino
hydrogen atom
compound according
Prior art date
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EP91311254A
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German (de)
English (en)
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EP0489579A1 (fr
Inventor
John Robert Porter
Thomas Andrew Millican
John Richard Morphy
Nigel Robert Arnold Beeley
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Celltech Therapeutics Ltd Te Slough Groot-Bri
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Celltech R&D Ltd
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Priority claimed from GB909026251A external-priority patent/GB9026251D0/en
Priority claimed from GB919110339A external-priority patent/GB9110339D0/en
Priority claimed from GB919110338A external-priority patent/GB9110338D0/en
Priority claimed from GB919112901A external-priority patent/GB9112901D0/en
Priority claimed from GB919112888A external-priority patent/GB9112888D0/en
Priority claimed from GB919115038A external-priority patent/GB9115038D0/en
Priority claimed from GB919115039A external-priority patent/GB9115039D0/en
Priority claimed from GB919115916A external-priority patent/GB9115916D0/en
Application filed by Celltech R&D Ltd filed Critical Celltech R&D Ltd
Publication of EP0489579A1 publication Critical patent/EP0489579A1/fr
Priority to IE921610A priority Critical patent/IE70429B1/en
Publication of EP0489579B1 publication Critical patent/EP0489579B1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C07K5/06113—Asp- or Asn-amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • This invention relates to a particular class of peptidyl derivatives, to processes for their preparation and to their use in medicine.
  • cellular connective tissue synthesis is offset by extracellular matrix degradation, the two opposing effects existing in dynamic equilibrium.
  • Degradation of the matrix is brought about by the action of proteinases released from resident connective tissue cells and invading inflammatory cells, and is due, in part, to the activity of at least three groups of metalloproteinases. These are the collagenases, the gelatinases (or type-IV collagenases) and the stromelysins.
  • these catalbolic enzymes are tightly regulated at the level of their synthesis and secretion and also at the level of their extracellular activity, the latter through the action of specific inhibitors, such as ⁇ 2-macroglobulins and TIMP (tissue Inhibitor of metalloproteinase) which form inactive complexes with metalloproteinases.
  • specific inhibitors such as ⁇ 2-macroglobulins and TIMP (tissue Inhibitor of metalloproteinase) which form inactive complexes with metalloproteinases.
  • hydroxamic acid peptidyl derivatives [see for example European Patent Specifications Nos. 214639, 231081, 236872 and 274453 and International Patent Specifications Nos. WO90/05716 and WO90/05719], have been described as collagenase and/or stromelysin inhibitors.
  • Tumour cell gelatinase in particular, has been associated with the potential of tumour cells to invade and metastasise. Tumour invasion and metastasis is the major cause of treatment failure for cancer patients, and the use of a selective gelatinase inhibitor such as a compound of the present invention which is capable of inhibiting tumour cell invasion can be expected to improve the treatment of this disease.
  • R represents a -CONHOH, carboxyl (-CO2H) or esterified carboxyl group
  • R' represents a hydrogen atom or an optionally substituted alkyl, alkenyl, aryl, aralkyl, heteroaralkyl or heteroarylthioalkyl group
  • R2 represents an optionally substituted phenylethyl, phenylpropyl or phenylbutyl group
  • R3 represents a hydrogen atom or an alkyl group
  • R4 represents a hydrogen atom or an alkyl group
  • R5 represents an optionally substituted alkyl or alkenyl group optionally interrupted by one or more -O- or -S- atoms or -N(R7)- groups [where R7 is a hydrogen atom or a C1 ⁇ 6alkyl group]
  • X represents an amino (-NH2), or substituted amino, hydroxyl or substituted hydroxyl group, provided
  • the compounds according to the invention can contain one or more asymmetrically substituted carbon atoms, for example those marked with an asterisk in formula (I).
  • the presence of one or more of these aysmmetric centres in a compound of formula (I) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereoisomers, and mixtures, including racemic mixtures, thereof.
  • the ⁇ line is used at a potential asymmetric centre to represent the possibility of R- and S- configurations, the line and the ------- line to represent an unique configuration at an asymmetric centre.
  • R when the group R represents an esterified carboxyl group, it may be for example a group of formula - CO2R8 where R8 is a straight or branched, optionally substituted C1 ⁇ 8alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; a C6 ⁇ 12arylC1 ⁇ 8alkyl group such as an optionally substituted benzyl, phenylethyl, phenylpropyl, ⁇ -naphthylmethyl or ⁇ -naphthylmethyl group; a C6 ⁇ 12aryl group such as an optionally substituted phenyl, ⁇ -naphthyl or ⁇ -naphthyl group; a C6 ⁇ 12aryloxyC1 ⁇ 8alkyl group such as an optionally substituted
  • Optional substituents present on the groups R8 include for example one or more halogen atoms such as fluorine, chlorine, bromine or iodine atoms, or C1 ⁇ 4alkyl, e.g. methyl or ethyl, or C1 ⁇ 4alkoxy, e.g. methoxy or ethoxy, groups.
  • halogen atoms such as fluorine, chlorine, bromine or iodine atoms
  • C1 ⁇ 4alkyl e.g. methyl or ethyl
  • C1 ⁇ 4alkoxy e.g. methoxy or ethoxy
  • group R represents an esterified carboxyl group, it may be a metabolically labile ester of a carboxylic acid.
  • group R1 in compounds of formula (I) represents an optionally substituted alkyl or alkenyl group
  • it may be, for example, a straight or branched C1 ⁇ 6 alkyl or C2 ⁇ 6alkenyl group, such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, n-hexyl, ethenyl, 1-propenyl, 1-butenyl or 2-butenyl group optionally substituted by one or more C1 ⁇ 6alkoxy, e.g.
  • C1 ⁇ 6alkylthio e.g. methylthio, ethylthio or propylthio
  • C6 ⁇ 12arylC1 ⁇ 6alkoxy e.g. phenylC1 ⁇ 6 alkoxy such as benzyloxy
  • aralkylthio e.g phenylC1 ⁇ 6alkylthio such as benzylthio
  • amino (-NH2) substituted amino, [such as -NHR9, where R9 is a C1 ⁇ 6 alkyl e.g. methyl or ethyl], C6 ⁇ 12arylC1 ⁇ 6alkyl, e.g.
  • phenylC1 ⁇ 6alkyl such as benzyl, C6 ⁇ 12aryl, e.g. phenyl, C3 ⁇ 8cycloalkyl, e.g. cyclohexyl, or C3 ⁇ 8cycloalkylC1 ⁇ 6alkyl, e.g. cyclohexylmethyl group], carboxyl (-CO2H) or -CO2R8 [where R8 is as defined above] groups.
  • Aryl groups represented by R1 in compounds of formula (I) include C6 ⁇ 12 aryl groups such as phenyl or ⁇ - or ⁇ -naphthyl groups.
  • Aralkyl groups represented by R1 include C6 ⁇ 12arylC1 ⁇ 6alkyl groups such as phenylC1 ⁇ 6alkyl, or ⁇ - or ⁇ -naphthylC1 ⁇ 6alkyl, for example benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, ⁇ - or ⁇ -naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl or naphthylpentyl groups.
  • C6 ⁇ 12arylC1 ⁇ 6alkyl groups such as phenylC1 ⁇ 6alkyl, or ⁇ - or ⁇ -naphthylC1 ⁇ 6alkyl, for example benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, ⁇ - or ⁇
  • the group R1 in compounds of formula (I) is a heteroaralkyl group, it may be for example a C3 ⁇ 6heteroarylC1 ⁇ 6alkyl group, such as an optionally substituted pyrrolylmethyl, furanylmethyl, thienylmethyl, imidazolylmethyl, oxazolylmethyl, thiazolylmethyl, pyrazolylmethyl, pyrrolidinylmethyl, pyridinylmethyl, pyrimidinylmethyl, morpholinylmethyl, or piperazinylmethyl group.
  • a heteroaralkyl group such as an optionally substituted pyrrolylmethyl, furanylmethyl, thienylmethyl, imidazolylmethyl, oxazolylmethyl, thiazolylmethyl, pyrazolylmethyl, pyrrolidinylmethyl, pyridinylmethyl, pyrimidinylmethyl, morpholinylmethyl, or piperazinylmethyl group.
  • Heteroarylthioalkyl groups represented by R1 include C3 ⁇ 6heteroarylthioC1 ⁇ 6alkyl groups such as optionally substituted pyrrolylthiomethyl, furanylthiomethyl, oxazolylthiomethyl, thiazolylthiomethyl, pyrazolylthiomethyl, pyrrolidinylthiomethyl, pyridinylthiomethyl, pyrimidinylthiomethyl, morpholinylthiomethyl, or piperazinylthiomethyl groups.
  • the aryl, aralkyl, heteroaralkyl, or heterarythioalkyl groups represented by R1, and the groups represented by R2 in compounds of formula (I) may each optionally be substituted in the cyclic part of the group by one, two or more substituents [R10] selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or C1 ⁇ 6alkyl, e.g. methyl or ethyl, C1 ⁇ 6alkoxy e.g. methoxy or ethoxy, C2 ⁇ 6alkylenedioxy, e.g. ethylenedioxy, haloC1 ⁇ 6alkyl, e.g.
  • substituents [R10] selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or C1 ⁇ 6alkyl, e.g. methyl or ethyl, C
  • C1 ⁇ 6alkylamino e.g. methylamino or ethylamino
  • C1 ⁇ 6dialkylamino e.g. dimethylamino or diethylamino
  • amino (-NH2 ) nitro, cyano, hydroxyl (-OH), carboxyl (-CO2H), -CO2R8, where R8 is as defined above, C1 ⁇ 6alkylcarbonyl, e.g. acetyl, sulphonyl (-SO2H), C1 ⁇ 6alkylsulphonyl, e.g.
  • methylsulphonyl aminosulphonyl (-SO2NH2), C1 ⁇ 6 alkylaminosulphonyl, e.g. methylaminosulphonyl of ethylaminosulphonyl, C1 ⁇ 6dialkylaminosulphonyl e.g. dimethylaminosulphonyl or diethylaminosulphonyl, carboxamido (-CONH2), C1 ⁇ 6alkylaminocarbonyl, e.g. methylaminocarbonyl or ethylaminocarbonyl, C1 ⁇ 6dialkylaminocarbonyl, e.g.
  • R10 substituents may be present at any ring carbon atom away from that attached to the rest of the molecule of formula (I).
  • any substituents may be present at the 2-, 3-or 4- 5- or 6- positions relative to the ring carbon atom attached to the remainder of the molecule.
  • groups R3 and R4 in compounds of formula (I) are alkyl groups, they may be for example C1 ⁇ 6alkyl groups such as methyl or ethyl groups.
  • the group R5 in compounds of formula (I) may be an optionally substituted straight or branched C1 ⁇ 6alkyl, e.g. methyl, ethyl, n-propyl i-propyl, n-butyl, i-butyl, n-pentyl or n-hexyl or C2 ⁇ 6alkenyl e.g. ethenyl or 1-propenyl group optionally interrupted by one or more -O- or -S- atoms or -N(R7)- groups where R7 is a hydrogen atom or a C1 ⁇ 6alkyl group such as a methyl group.
  • C1 ⁇ 6alkyl e.g. methyl, ethyl, n-propyl i-propyl, n-butyl, i-butyl, n-pentyl or n-hexyl or C2 ⁇ 6alkenyl e.g. etheny
  • Optional substituents which may be present on alkyl or alkenyl groups R5 include C6 ⁇ 12arylC1 ⁇ 6alkyl groups such as optionally substituted phenylC1 ⁇ 6 e.g. benzyl groups, C6 ⁇ 12arylC1 ⁇ 6alkoxy groups such as optionally substituted phenylC1 ⁇ 6alkoxy e.g. benzyloxy groups, C6 ⁇ 12aryl e.g. optionally substituted phenyl groups, C3 ⁇ 8heteroaryl e.g. optionally substituted indole, imidazole or quinoline groups, C6 ⁇ 12arylC1 ⁇ 6alkoxyC6 ⁇ 12aryl, e.g.
  • the optional substituents present on these groups may be R10 substituents as discussed above.
  • X in the compounds of formula (I) represents a substituted amino group it may be for example a group of formula -NR11R12, where R11 and R12, which may be the same or different, is each a hydrogen atom (with the proviso that when one of R11 or R12 is a hydrogen atom, the other is not) or an optionally substituted straight ot branched alkyl group, optionally interrupted by one or more -O- or -S- atoms or -N(R7)- or aminocarbonyloxy [-NHC(O)O-] groups or R11 and R12, together with the nitrogen atom to which they are attached, may form an optionally substituted C3 ⁇ 6cyclic amino group optionally possessing one or more other heteroatoms selected from -O- or - S-, or -N(R7)- groups.
  • R11 and/or R12 is an alkyl group it may be for example a C1 ⁇ 6alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl group, optionally interrupted by one or more -O- or -S- atoms, or - N(R7)- or aminocarbonyloxy groups and may be for example a methoxymethyl ethoxymethyl, ethoxymethyl, ethoxyethyl or ethylaminocarbonyloxymethyl group.
  • the optional substituents which may be present on such groups include hydroxyl (-OH), carboxyl (-CO2H), esterified carboxyl (-CO2R8), carboxamido (-CONH2), substituted carboxamido, e.g. a group -CONR11R12 where NR11R12 is as defined herein, amino (-NH2), substituted amino, for example a group of formula -NR11R12, or aryl, e.g. C6 ⁇ 12 aryl such a phenyl, optionally substituted by one, two or more R10 substituents selected from those listed above in relation to the group R2.
  • cyclic amino groups represented by -NR11R12 include morpholinyl, imidazolyl, piperazinyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, pyrrolidinyl, pyridinyl and pyrimidinyl groups.
  • group X is a substituted hydroxyl group it may be for example a group -OR11 where R11 is as defined above, other than a hydrogen atom.
  • Salts of compounds of formula (1) include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, such as hydrochlorides, hydrobromides, hydroiodides, p-toluene sulphonates, phosphates, sulphates, perchlorates, acetates, trifluoroacetates, propionates, citrates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
  • inorganic or organic acids such as hydrochlorides, hydrobromides, hydroiodides, p-toluene sulphonates, phosphates, sulphates, perchlorates, acetates, trifluoroacetates, propionates, citrates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
  • Salts may also be formed with bases.
  • Such salts include salts derived from inorganic or organic bases,. for example alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
  • R in compounds of the invention is an esterified carboxyl group
  • it may be a metabolically labile ester of formula -CO2R8 where R8 may be an ethyl, benzyl, phenylethyl, phenylpropyl, ⁇ - or ⁇ -naphthyl, 2,4-dimethylyphenyl, 4-t-butylphenyl, 2,2,2-trifluoroethyl, 1-(benzyloxy)benzyl, 1-(benzyloxy)ethyl, 2-methyl-1-propionyloxypropyl, 2,4,6-trimethylbenzoyloxymethyl or pivaloyloxymethyl group.
  • the group R1 may in particular be a C1 ⁇ 6alkyl group such as a methyl group, an aralkyl group such as benzyl group, an arylthioalkyl group such as a phenythiomethyl group or a heteroarylthioalkyl group such as thienylthiomethyl, pyridinylthiomethyl or pyrimidinylthiomethyl group or is especially a hydrogen atom.
  • the groups R3 and R4 in compounds of formula (I) may each in particular be a methyl group, or, especially, a hydrogen atom.
  • the group R5 in compounds of formula (I) may in particular be a C1 ⁇ 6alkyl group. e.g. an i-propyl or i-butyl group, or an optionally substituted benzyl, benzyloxybenzyl or indolymethyl group.
  • the group X in compounds of formula (I) may be in particular an amino (-NH2) or -NR11R12 group.
  • Particular -NR11R12 groups are -NHR12 groups.
  • Groups of this type include those where R12 is a C1 ⁇ 6alkyl group, for example a methyl, ethyl, or n-propyl group, optionally interrupted by one or more -O- or -S- atoms or -N(R7) [e.g. NH- or -N(CH3)-] or aminocarbonyloxy groups and optionally substituted by a hydroxyl, carboxyl, carboxyalkyl, e.g.
  • a particularly useful group of compounds according to the invention is that of formula (I) where R2 is an optionally substituted phenylpropyl group.
  • a further particularly useful group of compounds of formula (I) are those wherein X is an amino or substituted amino group.
  • R1, R3 and R4 is each preferably a hydrogen atom.
  • the group R in compounds according to the invention is a -CONHOH or a-CO2H group or a metabolically labile ester thereof.
  • R is a -CONHOH or a -CO2H group
  • An especially useful group of compounds according to the invention has the formula (Ia) wherein R, R2, R5 and X are as defined for formula (I); and the salts, solvates and hydrates thereof.
  • a particularly useful group of compounds of formula (Ia) are those wherein R represents a -CONHOH or -CO2H group; R2 represents an optionally substituted phenylpropyl group; X is an amino (-NH2) or substituted amino group; and the salts, solvates and hydrates thereof.
  • X may be a -NH2 group or a group - NR11R12 as defined for compounds of formula (I).
  • the group R5 may in particular be a C1 ⁇ 6alkyl group such as an i-propyl or i-butyl group, or an optionally substituted benzyl, benzyloxybenzyl or indolymethyl group.
  • the compounds according to the invention may be prepared by the following processes.
  • the groups R, R1, R2, R3, R4, R5 and X are as defined above, except where otherwise indicated.
  • functional groups such as amino, hydroxyl or carboxyl groups, present in the various compounds described below, and which it is desired to retain, may need to be in protected form before any reaction is initiated. In such instances, removal of the protecting group may be the final step in a particular reaction.
  • Suitable amino or hydroxyl protecting groups include benzyl, benzyloxycarbonyl or t-butyloxycarbonyl groups.
  • Suitable carboxyl protecting groups include benzyl groups, which may be removed from a protected derivative by the methods just discussed, or alkyl groups, such as a t-butyl group which may be removed from a protected derivative by treatment with trifluoroacetic acid in an aqueous solvent.
  • Suitable protecting groups and methods for their use will be readily apparent.
  • the formation of the protected amino, hydroxyl or carboxyl group may be achieved using standard alkylation or esterification procedures, for example as described below.
  • a compound of formula (I) may be prepared by coupling an acid of formula (II) or an active derivative thereof, with an amine of formula (III) followed by removal of any protecting groups.
  • Active derivatives of acids for formula (II) include for example acid anhydrides, or acid halides, such as acid chlorides.
  • the coupling reaction may be performed using standard conditions for amination reactions of this type.
  • the reaction may be achieved in a solvent, for example an inert organic solvent such as an ether, e.g. a cyclic ether such a tetrahydrofuran, an amide e.g. a substituted amide such as dimethylformamide, or a halogenated hydrocarbon such as dichloromethane at a low temperature, e.g. -30°C to amibient temperature, such as -20°C to 0°C, optionally in the presence of a base, e.g. an organic base such as an amine, e.g.
  • the reaction may additionally be performed in the presence of a condensing agent, for example a diimide such as N,N'-dicyclohexylcarbodiimide, advantageously in the presence of a triazole such as I-hydroxybenzotriazole.
  • a condensing agent for example a diimide such as N,N'-dicyclohexylcarbodiimide, advantageously in the presence of a triazole such as I-hydroxybenzotriazole.
  • the acid may be reacted with a chloroformate for example ethylchloroformate, prior to reaction with the amine of formula (III).
  • Free hydroxyl or carboxyl groups in the starting materials of formulae (II) [where R is -CONHOH or CO2H] and (III) may need to be protected during the coupling reaction. Suitable protecting groups and methods for their removal may be those mentioned above.
  • a compound of formula (Ia) may be prepared by reaction of a compound of formula (IIa) with an amine of formula (IIIa) as described above
  • Intermediate acids of formula (II) wherein R is a carboxyl or esterified carboxyl group may be prepared by hydrolysing a corresponding ester of formula (IV) where R13 is an alkyl group, for example a methyl or t-butyl group, using for example trifluoroacetic acid, or, when R13 is a methyl group using enzymatic hydrolysis, such as for example with ⁇ -chymotrypsin, in an aqueous solvent.
  • enzymatic hydrolysis usefully provides a method of isomer selection.
  • the ester of formula (IV) may be prepared by esterification of the corresponding acid of formula (V) using an appropriate acyl halide, for example an acyl chloride in a solvent such as an alcohol, e.g. methanol at a low temperature, e.g. around O°C.
  • an appropriate acyl halide for example an acyl chloride in a solvent such as an alcohol, e.g. methanol at a low temperature, e.g. around O°C.
  • Acids of formula (V) may be prepared by alkylation of a compound of formula (VI) with an appropriate halide, e.g. a compound R2Hal, where Hal is a halogen atom such as a chlorine or bromine atom in the presence of a base, for example an alkoxide such as sodium ethoxide in a solvent such as an alcohol, e.g. ethanol at ambient temperature, followed by decarboxylation using for example concentrated hydrochloric acid at an elevated temperature, e.g. the reflux temperature.
  • an appropriate halide e.g. a compound R2Hal, where Hal is a halogen atom such as a chlorine or bromine atom in the presence of a base, for example an alkoxide such as sodium ethoxide in a solvent such as an alcohol, e.g. ethanol at ambient temperature
  • decarboxylation using for example concentrated hydrochloric acid at an elevated temperature, e.g. the reflux temperature.
  • Intermediate acids of formula (IV) wherein R is a -CONHOH group or a protected derivative thereof may be prepared by reaction of an anhydride of formula (VII) with a hydroxylamine such as O-benzylhydroxylamine in a solvent such as tetrahydrofuran at a low temperature, e.g. around -20°C, followed where desired by removal of the protecting group as described above.
  • a hydroxylamine such as O-benzylhydroxylamine
  • a solvent such as tetrahydrofuran
  • the intermediate anhydrides of formula (VII) may be prepared for example by heating for example at the reflux temperature, a diacid of formula (V) where R is -CO2H with an acyl chloride such as acetyl chloride.
  • the homochiral acids of formula (IIa) may be prepared according to another feature of the invention by oxidation of an oxazolidinone of formula (VIII) (where Ph is a phenyl group) using an oxidising agent such as peroxide, e.g. hydrogen peroxide in a solvent such as an ether e.g. a cyclic ether such as tetrahydrofuran, at a low temperature, e.g. around 0°C followed by treatment with a base, such as lithium hydroxide, at an elevated temperature.
  • an oxidising agent such as peroxide, e.g. hydrogen peroxide in a solvent such as an ether e.g. a cyclic ether such as tetrahydrofuran, at a low temperature, e.g. around 0°C followed by treatment with a base, such as lithium hydroxide, at an elevated temperature.
  • the compounds of formula (VIII) are novel, particularly useful, intermediates for the preparation of stereoisomers of formula (Ia).
  • the compounds of formula (VIII) may be prepared by reaction of an acyl halide RCH2CH(R2)COHal (where Hal is a halogen atom such as chloride, bromine or iodine atom) with a solution of (S)-4-(phenylmethyl)-2-oxazolidinone in the presence of a base such as n-butyl lithium in a solvent such as tetrahydrofuran at a low temperature, e.g. around -78°C.
  • RCH2 CH)(R2)COHal may be prepared by treatment of the corresponding known acids RCH2CH(R2)CO2H with conventional halogenating agents for example thionyl halides under standard reaction conditions.
  • a compound of formula (I) where R is a carboxyl group may be prepared by decarboxylation of a corresponding compound of formula (IX).
  • the reaction may be achieved using standard conditions, for example by heating a compound of formula (IX) in an inert solvent, such as an aromatic hydrocarbon, e.g. xylene, at the reflux temperature.
  • an inert solvent such as an aromatic hydrocarbon, e.g. xylene
  • the intermediate acids of formula (IX) may be prepared by reaction of a protected acid of formula (X) where R is a protected carboxyl group such as a benzyloxycarbonyl group and Z1 is a protecting group such as a benzyl group with an amine of formula (III) using reagents and conditions as described above for coupling compounds of formula (II) and (III), followed by removal of the protecting groups.
  • the intermediates of formula (X) may be prepared by treatment of an appropriate malonic ester RCH2CO2Z1 with a halide of formula (XI) (where Hal is a halogen atom, e.g. a chlorine or bromine atom) in the presence of a base such as potassium t-butoxide in a solvent such as dimethylformamide at ambient temperature.
  • a halogen atom e.g. a chlorine or bromine atom
  • Halides of formula (XI) may be prepared by halogenation and subsequent decarboxylation of a di-acid of formula (XII). using for example a halogenating agent such as bromine in a solvent such as diethyl ether at ambient temperature, followed by heating of the resulting halogenated intermediate in a solvent such as an aromatic hydrocarbon e.g. xylene, at the reflux temperature.
  • a halogenating agent such as bromine in a solvent such as diethyl ether at ambient temperature
  • a solvent such as an aromatic hydrocarbon e.g. xylene
  • Intermediates of formula (XII) may be prepared by hydrolysis of the corresponding di-alkylester (e.g. the dimethyl or diethyl ester) using a base such as sodium or potassium hydroxide in a solvent such as an alcohol e.g. methanol at the reflux temperature.
  • the di-alkyl ester starting materials are either known compounds or may be prepared by methods analogous to those used for the preparation of the known compounds, for example as described in the Examples herein.
  • a compound of formula (I) wherein R is a -CONHOH group may be prepared by reaction of a corresponding acid of formula (I) wherein R is a -CO2H group or an active derivate thereof (for example an acid chloride or an acid anhydride) with hydroxylamine or an O-protected derivative or a salt thereof.
  • the reaction may be performed using the reagents and conditions described above in the preparation of compounds of formula (I) from the starting materials of formulae (II) and (III).
  • compounds of formula (I) wherein R is - CO2H and/or X contains a -CO2H group may be prepared by hydrolysis of the corresponding esterified compounds (for example where R is a -CO2R8 group and/or X contains a similar group) using conventional procedures, for example by treatment with a base, e.g. an alkali metal hydroxide such as lithium hydroxide in a solvent such as an aqueous alcohol, e.g. aqueous methanol, or by treatment with an acid such as a mineral acid, e.g. hydrochloric acid in the presence of a solvent, e.g. dioxan.
  • a base e.g. an alkali metal hydroxide such as lithium hydroxide in a solvent such as an aqueous alcohol, e.g. aqueous methanol
  • an acid such as a mineral acid, e.g. hydrochloric acid in the presence of a solvent, e.g. diox
  • esters of formula (I), for example where R is a CO2R8 group and/or X contains a -CO2R8 group may be prepared by reaction of the corresponding acids, where R is a -CO2H group and/or X contains a -CO2H group or an active derivative thereof, with an alcohol R8OH using standard conditions.
  • the compounds according to the invention are potent and selective inhibitors of gelatinase.
  • the activity and selectivity of the compounds may be determined by the use of appropriate enzyme inhibition test for example as described in Example A hereinafter.
  • compounds according to the invention have been shown to inhibit gelatinase with Ki values in the picomolar-nanomolar range and to have around a 40 fold or greater selectivity for gelatinase over stromelysin, and around a 20-fold or greater selectivity for gelatinase over collagenase.
  • nude mice may be inoculated with a tumour cell line showing gelatinase - dependent invasion and the ability of compounds according to the invention to reduce subsequent lung tumour colonisation may be evaluated in accordance with standard procedures.
  • compounds according to the invention when administered intravenously at 1mg/kg to mice in the above model have reduced lung tumour colonisation to negligable levels.
  • the compounds according to the invention can be expected to be of use to prevent tumour cell metastasis and invasion.
  • the compounds may therefore be of use in the treatment of cancer, particularly in conjunction with radiotherapy, chemotherapy or surgery, or in patients presenting with primary tumours, to control the development of tumour metastasises.
  • Particular cancers may include breast, melanoma, lung, head, neck or bladder cancers.
  • the compounds of formula (I) may be formulated in a conventional manner, optionally with one or more physiologically acceptable carriers, diluents or excipients.
  • composition comprising a compound of formula (I) and a pharmaceutically acceptable diluent, carrier or excipient.
  • the invention provides a process for the production of a pharmaceutical composition
  • a process for the production of a pharmaceutical composition comprising bringing a compound of formula (I) into association with a pharmaceutically acceptable diluent, carrier or excipient.
  • Compounds for use according to the present invention may be formulated for oral, buccal, parental or rectal administration or in a form suitable for nasal administration or administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glycollate
  • wetting agents
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles; and preservatives.
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds of formula (I) may be formulated for parental administration by injection e.g. by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form.
  • the compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds of formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds of formula (I) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
  • the compounds for use according to the present invention are conventiently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispenser device may be accompanied by instructions for admininstration.
  • doses of compounds of formula (I) used to control the development of tumour metastasises will vary depending on the condition of the patient to be treated but in general may be in the range around 0-5mg to 50mg/kg body weight, particularly from about 1mg to 40mg/kg body weight. Dosage units may be varied according to the route of administration of the compound in accordance with conventional practice.
  • Sodium ethoxide was prepared by adding sodium metal (2.5g, 108mmoL) to anhydrous ethanol (150ml) under nitrogen. Triethyl 1,1,2-ethanetricarboxylate (26.6g, 25ml, 108mmoL) was added and the mixture stirred at room temperature (RT) for 20 minutes. Isobutyl bromide (19.12g, 15ml, 108mmoL) was added dropwise over 1 hour and the solution raised to reflux overnight. The precipitated sodium bromide was filtered off and the filtrate concentrated in vacuo. The residue was treated with cold H2O (200ml) and extracted with diethyl ether (3 x 100ml).
  • the acid M (502mg, 1.8mmoL) was dissolved in dry THF (20ml) and cooled to -20°C. Ethylchloroformate (245mg, 233»l, 1.8mmoL) and N-methyl morpholine was added and the suspension left for 1 hour at -20°C. A DMF solution (10ml) of L-valine-L-alanine amide (500mg) was added dropwise. Once the addition was completed the cooling bath was removed and the reaction allowed to warm up to room temperature overnight. The organic solution was poured into 10% HCl and extracted with ethyl acetate (x3). The organic layer was dried (MgSO4) and concentrated in vacuo to give a solid.
  • the activity and selectivity of the compounds of the invention may be determined as described below.
  • enzyme e.g. gelatinase, stromelysin, collagenase
  • a range of inhibitor concentrations 0.1-50 x Ki
  • substrate approximately 20»m
  • enzyme e.g. gelatinase, stromelysin, collagenase
  • enzyme e.g. gelatinase, stromelysin, collagenase
  • a range of inhibitor concentrations 0.1-50 x Ki
  • substrate approximately 0.1M
  • Brij 35 at either room temperature or 37°C depending on the enzyme.
  • the reaction is stopped by adjusting the pH to 4 using 0.1M sodium acetate buffer and the fluorescence read at an excitation wavelength of 280nm and emission wavelength of 346nm.
  • K i values can be established using the equation for tight-being inhibition:- where V o is the initial rate of reaction in the absence of inhibitor, V i is the initial rate in the presence of inhibitor, [E] is the total enzyme concentration and [I] the total inhibitor concentration in the reaction mixture.
  • K i (app) was assumed to approximate to the true K i as [S] « Km for the substrate hydrolysis.
  • K i was determined by performing the analyses at several substrate concentrations. A plot of K i (app) vs. [S] then gave the true K i as the value of the y-axis intercept.

Claims (19)

  1. Composé de formule (1) :
    Figure imgb0031
     dans laquelle R est un radical -CONHOH, carboxyle (-CO₂H) ou carboxyle estérifié ;
       R¹ est un atome d'hydrogène ou un groupe alkyle, alcényle, aryle, aralkyle, hétéroaralkyle ou hétéroarylthioalkyle éventuellement substitué ;
       R² est un groupe phényléthyle, phénylpropyle ou phénylbutyle éventuellement substitué ;
       R³ est un atome d'hydrogène ou un groupe alkyle ;
       R⁴ est un atome d'hydrogène ou un groupe alkyle ;
       R⁵ est un groupe alkyle ou alcényle éventuellement substitué, éventuellement interrompu par un ou plusieurs atomes -O- ou -S- ou groupes -N(R⁷)- [où R⁷ est un atome d'hydrogène ou un groupe alkyle en C₁₋₆] ;
       X est un groupe amino (-NH₂) ou encore amino substitué, hydroxyle ou hydroxyle substitué, du moment que X n'est pas un radical méthylamino quand R² est le radical phényléthyle ;
       et ses sels, produits de solvatation et hydrates.
  2. Composé selon la revendication 1, dans lequel R est un groupe -CONHOH ou carboxyle (-CO₂H).
  3. Composé selon les revendications 1 ou 2, dans lequel chacun des radicaux R¹, R³ et R⁴ est un atome d'hydrogène.
  4. Composé selon l'une quelconque des revendications 1 à 3, dans lequel R⁵ est un groupe alkyle en C₁₋₆ ou alcényle en C₂₋₆ à chaîne droite ou ramifiée, éventuellement interrompu par un ou plusieurs atomes -O- ou -S- ou groupes -N(R⁷)- [où R⁷ est un atome d'hydrogène ou un groupe alkyle en C₁₋₆], et éventuellement substitué par un groupe aryl(en C₆₋₁₂) alkyle(en C₁₋₆), aryl(en C₆₋₁₂)alcoxy (en C₁₋₆), aryle en C₆₋₁₂, hétéroaryle en C₃₋₈, aryl (en C₆₋₁₂) alcoxy (en C₁₋₆) aryle (en C₆₋₁₂), -OH, -SH, alkylthio en C₁₋₆, carboxyle (-CO₂H), amino (-NH₂), carboxamido (-CONH₂) ou guanido -NHC(NH₂)=NH.
  5. Composé selon l'une quelconque des revendications 1 à 4, dans lequel R² est un groupe phénylpropyle éventuellement substitué.
  6. Composé selon l'une quelconque des revendications précédentes, dans lequel X est un groupe amino ou amino substitué.
  7. Composé de formule (1a)
    Figure imgb0032
     dans laquelle R est un groupe -CONHOH, carboxyle (-CO₂H) ou carboxyle estérifié ;
       R² est un groupe phénylpropyle éventuellement substitué ;
       R⁵ est un groupe alkyle ou alcényle éventuellement substitué, éventuellement interrompu par un ou plusieurs atomes -O- ou -S- ou groupes -N(R⁷)- [où R⁷ est un atome d'hydrogène ou un groupe alkyle en C₁₋₆] ; et
       X est un groupe amino (-NH₂) ou encore amino substitué, hydroxyle ou hydroxyle substitué ; et ses sels, produits de solvatation et hydrates.
  8. Composé selon la revendication 7, dans lequel R représente un groupe carboxyle (-CO₂H).
  9. Composé selon la revendication 7, dans lequel R est un groupe -CONHOH.
  10. Composé selon les revendications 7 à 9, dans lequel R⁵ est un groupe alkyle en C₁₋₆ ou alcényle en C₂₋₆ à chaîne droite ou ramifiée.
  11. Composé selon les revendications 7 à 9, dans lequel R⁵ est un groupe alkyle en C₁₋₆ ou alcényle en C₂₋₆ à chaîne droite ou ramifiée, interrompu par un ou plusieurs atomes -O- ou -S- ou groupes -N(R⁷)-, où R⁷ est un atome d'hydrogène ou un groupe alkyle en C₁₋₆.
  12. Composé selon l'une quelconque des revendications 7 à 9, dans lequel R⁵ est un groupe alkyle en C₁₋₆ ou alcényle en C₂₋₆ à chaîne droite ou ramifiée, éventuellement interrompu par un ou plusieurs atomes -O- ou -S- ou groupes -N(R⁷)- [où R⁷ est un atome d'hydrogène ou un groupe alkyle en C₁₋₆], et éventuellement substitué par un groupe aryl (en C₆₋₁₂) alkyle (en C₁₋₆), aryl (en C₆₋₁₂) alcoxy (en C₁₋₆), aryle en C₆₋₁₂, hétéroaryle en C₃₋₈, aryl (en C₆₋₁₂) alcoxy (en C₁₋₆), alcoxy en C₁₋₆, aryle en C₆₋₁₂, -OH, -SH, alkylthio en C₁₋₆, carboxyle (-CO₂H), amino (-NH₂), carboxamido (-CONH₂) ou guanido -NHC(NH₂)=NH.
  13. Composé selon les revendications 7 à 12, dans lequel X est -NH₂.
  14. Composé selon les revendications 7 à 12, dans lequel X est un groupe -NHR¹² où R¹² est un groupe alkyle en C₁₋₆ éventuellement interrompu par un ou plusieurs atomes -O- ou -S- ou groupes aminocarbonyloxy et éventuellement substitué par des groupes hydroxyle, carboxyle, carboxyalkyle, carboxamido, amino, di(alkyle en C₁₋₆)amino, alkylamino en C₁₋₆, (hydrocarbure cyclique en C₃₋₆)amino ou des groupes phényle éventuellement substitués.
  15. Composé selon les revendications 7 à 12, dans lequel X est un groupe -NR¹¹R¹² où R¹¹ et R¹² sont identiques ou différents et sont chacun un atome d'hydrogène (du moment que, quand l'un des radicaux R¹¹ ou R¹² est un atome d'hydrogène, l'autre ne l'est pas), ou un groupe alkyle à chaîne droite ou ramifiée, éventuellement substitué, éventuellement interrompu par un ou plusieurs atomes -O- ou -S- ou groupes -N(R⁷)- [où R⁷ est un atome d'hydrogène ou un groupe alkyle en C₁₋₆] ou aminocarbonyloxy [-NHC(O)O-], ou bien R¹¹ et R¹², avec l'atome d'azote auquel ils sont liés, forment un groupe (hydrocarbure cyclique en C₃₋₆)amino éventuellement substitué, possédant éventuellement un ou plusieurs autres hétéroatomes choisis parmi -O- ou -S-, ou groupes -N(R⁷)- [où R⁷ est un atome d'hydrogène ou un groupe alkyle en C₁₋₆].
  16. Composé selon l'une quelconque des revendications 7 à 15, dans lequel R² est un groupe phénylpropyle.
  17. Composé selon l'une quelconque des revendications 7 à 16, dans lequel R² est un groupe phénylpropyle substitué dans la partie cyclique du groupe par un ou au moins deux atomes d'halogène ou groupes alkyle en C₁₋₆, alcoxy en C₁₋₆, alkylènedioxy en C₂₋₆, halogènalkyle en C₁₋₆, alkylamino en C₁₋₆, di(alkyle en C₁₋₆)amino, amino -(NH₂), nitro, cyano, hydroxyle (-OH), carboxyle (-CO₂H), carboxyle estérifié, alkyl (en C₁₋₆)carbonyle, sulfonyle (-SO₂H), alkylsulfonyle en C₁₋₆, aminosulfonyle (-SO₂NH₂), alkyl (en C₁₋₆)aminosulfonyle, di(alkyle en C₁₋₆)aminosulfonyle, carboxamido (-CONH₂), alkyl (en C₁₋₆)aminocarbonyle, di(alkyle en C₁₋₆)aminocarbonyle, sulfonylamino (-NHSO₂H), alkyl (en C₁₋₆)sulfonylamino ou encore di(alkyle en C₁₋₆)sulfonylamino.
  18. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 17 et un diluant, excipient ou véhicule pharmaceutiquement acceptable.
  19. Procédé pour préparer un composé de formule (I) selon la revendication 1, ce procédé consistant :
    (a) à coupler un acide de formule (II)
    Figure imgb0033
     ou un de ses dérivés actifs et/ou protégés, avec une amine de formule (III)
    Figure imgb0034
     ou l'un de ses dérivés protégés, puis à éliminer les éventuels groupes protecteurs ; ou bien
    (b) à décarboxyler un composé de formule (IX)
    Figure imgb0035
     pour produire un composé de formule (I) dans laquelle R est un groupe -CO₂H ; et/ou
    (c) à procéder à une interconversion en un composé de formule (I).
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AU652596B2 (en) 1994-09-01
DE69108529T2 (de) 1995-11-30
DK0489579T3 (da) 1995-06-12
DE69108529D1 (de) 1995-05-04
EP0489577B1 (fr) 1995-03-22
NO922968L (no) 1992-09-24
AU9023391A (en) 1992-06-25
JPH05503719A (ja) 1993-06-17
US5300501A (en) 1994-04-05
FI923495A0 (fi) 1992-08-03
EP0489577A1 (fr) 1992-06-10
GB2255340B (en) 1994-09-28
HUT61973A (en) 1993-03-29
ES2069833T3 (es) 1995-05-16
FI923495A (fi) 1992-08-03
GB2255339B (en) 1994-10-05
KR927003521A (ko) 1992-12-18
DE69108363D1 (de) 1995-04-27
KR927003520A (ko) 1992-12-18
AU652793B2 (en) 1994-09-08
GB9211715D0 (en) 1992-08-26
HU9202498D0 (en) 1992-10-28
CA2073513A1 (fr) 1992-06-04
NO922967D0 (no) 1992-07-28
EP0489579A1 (fr) 1992-06-10
HU9202497D0 (en) 1992-10-28
JPH05503720A (ja) 1993-06-17
HUT62263A (en) 1993-04-28
DE69108363T2 (de) 1995-08-31
ATE120182T1 (de) 1995-04-15
GB2255340A (en) 1992-11-04
FI923494A (fi) 1992-08-03
GR3015567T3 (en) 1995-06-30
GB9211714D0 (en) 1992-08-26
WO1992009564A1 (fr) 1992-06-11
AU9017391A (en) 1992-06-25
NO922968D0 (no) 1992-07-28
WO1992009565A1 (fr) 1992-06-11
CA2073510A1 (fr) 1992-06-04
NO922967L (no) 1992-09-24
FI923494A0 (fi) 1992-08-03
GB2255339A (en) 1992-11-04
ATE120451T1 (de) 1995-04-15

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